ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2-dependent migration
| Autor: | Claire Lacombe, Christophe Combadière, Virginie Felouzis, Camille Baudesson de Chanville, Benoît L. Salomon, Philippe Deterre, Sandrine Barthélémy, Christiane Quiniou, Sandrine Sagan, Patricia Hermand, Christophe Piesse, Sylvain Chemtob, Constance Auvynet, Ludovic Carlier, Karim Dorgham, Florian Sennlaub, Charlotte Pouchy, Lucie Poupel |
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| Přispěvatelé: | Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ligue Nationnale Contre le Cancer, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de psychiatrie et neurosciences (U894 / UMS 1266) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Models Molecular 0301 basic medicine CCR2 Encephalomyelitis Autoimmune Experimental Protein Conformation Receptors CCR2 Allosteric regulation Peptide CHO Cells Biochemistry Mice 03 medical and health sciences Chemokine receptor Cricetulus Cell Movement [ CHIM.ORGA ] Chemical Sciences/Organic chemistry Genetics Animals Humans Molecular Biology Chemokine CCL2 ComputingMilieux_MISCELLANEOUS Mice Knockout chemistry.chemical_classification Oligopeptide [CHIM.ORGA]Chemical Sciences/Organic chemistry Chemotaxis Ligand (biochemistry) Molecular biology 3. Good health 030104 developmental biology Gene Expression Regulation chemistry Female CC chemokine receptors Oligopeptides Protein Binding Biotechnology |
| Zdroj: | FASEB Journal FASEB Journal, 2016, 30 (6), pp.2370-2381. ⟨10.1096/fj.201500116⟩ FASEB Journal, Federation of American Society of Experimental Biology, 2016, 30 (6), pp.2370-2381. 〈10.1096/fj.201500116〉 FASEB Journal, Federation of American Society of Experimental Biology, 2016, 30 (6), pp.2370-2381. ⟨10.1096/fj.201500116⟩ |
| ISSN: | 0892-6638 1530-6860 |
| DOI: | 10.1096/fj.201500116⟩ |
| Popis: | CC chemokine receptor type 2 (CCR2) is a key molecule in inflammatory diseases and is an obvious drug target for the treatment of inflammation. A number of nonpeptidic, competitive CCR2 antagonists have been developed, but none has yet been approved for clinical use. Our aim was to identify a short peptide that showed allosteric antagonism against human and mouse CCR2. On the basis of sequence analysis and 3-dimensional modeling, we identified an original 7-d-amino acid peptidic CCR2 inhibitor that we have called extracellular loop 1 inverso (ECL1i), d(LGTFLKC). In vitro, ECL1i selectively and potently inhibits CC chemokine ligand type 2 (CCL2)-triggered chemotaxis (IC50, 2 µM) but no other conventional CCL2-associated events. We used the classic competitive CCR2 antagonist, BMS22 {2-[(isopropylaminocarbonyl)amino]-N-[2-[[cis-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-(trifluoromethyl)benzamide}, as positive control and inhibited CCL2-dependent chemotaxis with an IC50 of 18 nM. As negative control, we used a peptide with the same composition as ECL1i, but in a different sequence, d(FKLTLCG). In vivo, ECL1i (4 mg/kg) interfered with CCR2-positive cell recruitment and attenuated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This study establishes ECL1i as the first allosteric inhibitor of CCR2 with functional selectivity. ECL1i is a promising new agent in therapeutic development, and it may, by its selective effect, increase our understanding of CCR2 signaling pathways and functions.-Auvynet, C., Baudesson de Chanville, C., Hermand, P., Dorgham, K., Piesse, C., Pouchy, C., Carlier, L., Poupel, L., Barthélémy, S., Felouzis, V., Lacombe, C., Sagan, S., Salomon, B., Deterre, P., Sennlaub, F., Combadière, C. ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2-dependent migration. |
| Databáze: | OpenAIRE |
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